CN104974059B - A kind of Rivaroxaban intermediate and preparation method thereof - Google Patents
A kind of Rivaroxaban intermediate and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of key intermediate synthesizing razaxaban, and the preparation method of this intermediate.Described intermediate is the compound (in formula III, X is chlorine or bromine) shown in formula III, and its preparation method is: with Isosorbide-5-Nitrae diaminobenzene and 2 (2 halo ethyoxyl) acetyl halide as initiation material, adds acid binding agent, obtains formula III compound after monosubstituted.Described intermediate is that the present invention obtains first, and prepares the method yield height of razaxaban through series reaction from this intermediate, and products therefrom purity is good, is suitably applied industrialized great production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, in particular to a kind of intermediate for synthesizing razaxaban and
Its preparation method.
Background technology
Thrombosis is the blood clotting of blood vessel local, and arterial thrombus can cause myocardial infarction, apoplexy, acute coronary
Syndrome and peripheral arterial disease etc., and phlebothrombosis can cause pulmonary infarction.Traditional anticoagulant heparin and Hua Fa
Woods is the conventional method treating and preventing Artery, Vein blood bolt, and clinical trial and clinical practice establish it and pass
The status of system anticoagulant.But heparin is parenteral, and patient dependence is poor, is not suitable for life-time service.Heparin needs
Antithrombase competence exertion effect to be had, invalid to the Xa factor in prothrombin complex, prolonged application has and causes
Osteoporosis and the thrombocytopenic danger of potential mediated by heparin.Warfarin onset is slow, needs heparin transition, INR
Easily fluctuating and unpredictable, the most easily interact with multiple food, dosage individual variation is bigger.
Razaxaban (Rivaroxaban) chemistry is entitled: the chloro-N-of 5-({ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)
Phenyl]-1,3-oxazolidine-5-base }-methyl)-2-thenoyl amine, its chemical structural formula is as follows:
Razaxaban (Rivaroxaban) is developed by Bayer A.G, is that first, the whole world can directly be administered orally
Xa factor inhibitor, is used for preventing and treating thrombosis.Razaxaban is the direct inhibitor of Xa factor of a kind of high selectivity,
By factor Xa anticoagulant thus stop the inherent and external path of coagulation cascade system, thus enzyme blood anticoagulant
The formation of bolt.
The synthetic route of present stage razaxaban mainly has following several:
Route one: the patent reaction scheme that razaxaban Yuan Yan company Bayer Bitterfeld GmbH has authorized in China is as follows:
The shortcoming of above-mentioned route needs during being to prepare intermediate a to use expensive palladium metal, and cost of material is high, simultaneously
Using hydrogen in production, relative risk is bigger.
Route two: WO2009023233 discloses and utilizes morpholine and be initiation material to fluorine nitro, through being condensed to yield 4-
Morpholine Nitrobenzol, then prepare 4-morpholine ketone group Nitrobenzol with potassium permanganate oxidation, then through the steps such as catalytic hydrogenation last with
2-chloro-thiophene-5-formyl chloride prepares razaxaban under pyridine is catalyzed, and its reaction scheme is as follows:
Said method synthetic route is longer, equally exists the mistake utilizing expensive palladium metal to carry out catalytic hydrogenating reduction nitro
Journey.
It is former that route three: US2007157456 and WO2006055951 reports with ethyl chloroacetate and ethylaminoethanol
Material, by following route synthesis razaxaban:
Route four: CN1852902A reports with aniline as raw material, prepares with 2-chloroethyl alcohol back flow reaction in aqueous
2-phenylamino ethanol, reacts prepared 4-phenyl-3-morpholone in the basic conditions with chloracetyl chloride, through nitrification, catalysis hydrogen
The steps such as change and epoxide open loop prepare razaxaban raceme, more chiral post splits and obtains razaxaban, instead
Answer route as follows:
Route three and route four are required for carrying out chiral separation, are not suitable for large-scale production；There is also simultaneously and want profit
Carry out the step of catalytic hydrogen reduction nitro by expensive heavy metal palladium, add cost of material and production cost.
Summary of the invention
For solving above-mentioned problems of the prior art, the present invention provides a kind of intermediate for synthesizing razaxaban
And the preparation method of this intermediate.
Specifically, the Rivaroxaban intermediate that the present invention provides is compound as shown in formula III:
X in above formula is halogen, preferably chlorine or bromine, more preferably chlorine.
Present invention also offers a kind of method preparing formula III compound: under suitable experiment condition, with Isosorbide-5-Nitrae-diaminourea
Benzene (Formulas I) and 2-(2-halo ethyoxyl) acetyl halide (Formula II) are initiation material, add acid binding agent, through monosubstituted
The compound shown in formula III is obtained after reaction, as follows:
In above-mentioned reaction equation, described X group is halogen, preferably chlorine or bromine, more preferably chlorine.
In above-mentioned preparation method, described acid binding agent can be pyridine or DMAP (DMAP), more preferably
Pyridine.
In above-mentioned preparation method, the non-matter such as oxolane, chloroform, dichloromethane, benzene, toluene and/or ether can be used
Sub-property solvent is as the solvent of described single substitution reaction, more preferably oxolane.
In above-mentioned preparation method, initiation material Isosorbide-5-Nitrae-diaminobenzene (Formulas I) and 2-(2-halo ethyoxyl) acetyl halide (formula
II) mol ratio is preferably 3～30: 1, more preferably 5～10: 1.Mol ratio crosses conference increases cost of material, mole
Ratio is too small, and disubstituted by-product can be caused to increase.
In above-mentioned preparation method, the reaction temperature of described single substitution reaction is 0 DEG C to 50 DEG C, and more preferably 10 DEG C are arrived
20℃。
Further, the above-mentioned method preparing formula III compound specifically may is that molten to Isosorbide-5-Nitrae-diaminobenzene and acid binding agent
In reaction dissolvent, then drip 2-(2-halo ethyoxyl) acetyl halide (Formula II) solution and react, time for adding
It is 1～10 hour, more preferably 2～5 hours.
The present invention compared with prior art has the advantage that
1. present invention firstly provides a kind of new Rivaroxaban intermediate N-(4-aminophenyl)-2-(2-halo ethyoxyl)
Acetamide (formula III) and preparation method thereof.
Wherein, described intermediate N (4-aminophenyl)-2-(2-halo ethyoxyl) acetamide (formula III) is that the present invention is first
Secondary obtaining, and described preparation method is easy and simple to handle, products therefrom purity is good, and yield is high, can be up to 85%
Left and right, the preferred version yield of the present invention can be up to more than 90% especially, is suitable for industrialized great production.
2. the formula III compound of the present invention can be used for preparing 4-(4-aminophenyl)-3-morpholone, thus provides one
Prepare the new method of 4-(4-aminophenyl)-3-morpholone.
Wherein, X is halogen chlorine or bromine.
N-(4-aminophenyl)-2-(2-halo ethyoxyl) acetamide (formula III) is carried out ring-closure reaction, obtains 4-(4-
Aminophenyl)-3-morpholone (formula IV).The purity of 4-(4-the aminophenyl)-3-morpholone that the method prepares is good, yield
Height, may be up to about 87%, and the particularly purity of the preferred technical scheme of the present invention may be up to more than 90%；And
Avoiding in preparation process uses expensive Metal Palladium to carry out nitro reduction, easy and simple to handle, is suitable for industrialized production.
3. the formula III compound of the present invention is further useful for preparing 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-
Oxazolidine-3-base] phenyl } morpholine-3-ketone (Formula VII), thus provide one and prepare 4-{4-[(5S)-5-(amino methyl)-2-
Oxo-1,3-oxazoles alkane-3-base] phenyl } new method of morpholine-3-ketone.
The intermediate 4-(4-aminophenyl)-3-morpholone (formula IV) prepared by formula III compound and (R)-2-(chloromethyl)
Oxirane generation ring-opening reaction prepare intermediate V, intermediate V again with phthalimide nak response prepare in
Mesosome VI, intermediate VI and N, N '-carbonyl dimidazoles reaction, then slough amido protecting, prepare razaxaban and close
Key intermediate VII.4-{4-[(5S)-5-(the amino methyl)-2-oxo-1,3-oxazolidine-3-base] phenyl that described method prepares }
The purity of morpholine-3-ketone is good, and yield is high, may be up to 61% from a mole total recovery for intermediate III to intermediate VII left
Right；And avoiding in preparation process uses expensive Metal Palladium to carry out nitro reduction, easy and simple to handle, is suitable for industrialization
Produce.
4. the formula III compound of the present invention is finally for preparing razaxaban, thus provides one and prepares profit and cut down sand
The new method of class.
Above-mentioned intermediate VII and 2-chloroformyl-5-chlorothiophene carry out substitution reaction, prepared razaxaban:
Based on the inventive method, the purity of the final razaxaban prepared is good；And the present invention avoids in preparation process
The Metal Palladium using costliness carries out nitro reduction, easy and simple to handle, is suitable for industrialized production.
5. being prepared the method route of razaxaban by formula III compound short, yield is high, pollutes little, and preparation process is avoided
Use expensive Metal Palladium to carry out nitro reduction, be suitable for industrialized production.
6. it is high that the formula III compound utilizing the present invention prepares razaxaban yield, prepares through series reaction from compound III
A mole total recovery for end product razaxaban may be up to about 52%.
Detailed description of the invention
Below by way of the description of detailed description of the invention, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art are according to the basic thought of the present invention, and various modifications may be made or improves, but as long as not
Depart from the basic thought of the present invention, the most within the scope of the present invention.
In the examples below, HPLC detection instrument can be that Shimadzu Corporation of (such as) Japan produces
Shimadzu LC-20A.The computational methods of purity use area normalization method；Purity and the assay method of ee value
Can be found in second annex VD of Chinese Pharmacopoeia (2010 editions)；The computing formula of molar yield is: (product molar number/
Main material molal quantity) × 100%.Mass Spectrometer Method instrument can be the API5500 type liquid of American AB SCIES company
Phase chromatograph-mass spectrometer.NMR detection instrument can be that the AM400MHZ type nuclear-magnetism of BRUKER company is total to
Vibration Meter.
In the examples below, Isosorbide-5-Nitrae-diaminobenzene is available from the happy Industrial Co., Ltd. of Shanghai Jin Jin；2-(2-chloro ethoxy
Base) chloroacetic chloride is available from Hangzhou Tuo Mu Science and Technology Ltd.；(R)-2-(chloromethyl) oxirane is available from Shanghai to prosperous
Chemical Co., Ltd.；Phthalimide potassium is available from Qingzhou City Olympic star Chemical Co., Ltd.；N, N '-carbonyl diurethane
Imidazoles is available from Shanghai to prosperous Chemical Co., Ltd.；2-chloroformyl-5-chlorothiophene is available from Shandong Rizhao Li Deshi science and technology to be had
Limit company.
The preparation of embodiment 1:N-(4-aminophenyl)-2-(2-Chloroethoxy) acetamide (formula III):
At the present embodiment, X=Cl in above-mentioned reaction equation.
Reaction bulb adds 194.7g(1.8mol) 1,4-diaminobenzene, 47.4g(0.6mol) pyridine and 900ml
Oxolane, stirs, and is cooled to 10 DEG C to 20 DEG C, is slowly added dropwise 2-(the 2-chlorine being dissolved in 300ml oxolane
For ethyoxyl) chloroacetic chloride 46.8g(0.3mol), dropping process temperature controls at 10 DEG C to 20 DEG C, and time for adding controls
At 5 hours, drip and finish, TLC is controlled (n-hexane: ethyl acetate: triethylamine=30:20:1, volume ratio) raw material and substantially disappears
Losing, stopped reaction, decompression (-0.1MPa～-0.09MPa) is evaporated off oxolane and reclaims the Isosorbide-5-Nitrae-diaminobenzene of excess,
Adding 600ml ethyl acetate and the mixed solvent of 300ml acetone, temperature rising reflux dissolves residual grease, is down to 10 DEG C
Left and right crystallize 5 hours, filters, decompression drying, obtains off-white color intermediate III product 61.8g, molar yield 90.4%,
HPLC purity 98.6%.
The detection data of the title product obtained by nuclear magnetic resonance, NMR and mass spectral analysis are as follows:1H NMR (400MHz,
CDCl3): δ=7.39 (d, 2H), 7.24(s, 1H), 6.59 (d, 2H), 6.25 (s, 2H), 4.30 (s, 2H), 3.83 (t,
2H), 3.66 (t, 2H)；13C NMR (75MHz, CDCl3): δ=169.2,144.1,128.5,122.3,122.3,116.5,
116.5,68.5,68.2,42.3ppm；HR-MS (ESI): C10H13ClN2O2Molecular weight: 228.1, [M+H]+Measured value:
229.7。
The preparation of embodiment 2:N-(4-aminophenyl)-2-(2-Chloroethoxy) acetamide (formula III):
Reaction bulb adds 129.8g(1.2mol) 1,4-diaminobenzene, 31.6g(0.4mol) pyridine and 600ml
Oxolane, stirs, and is cooled to 10 DEG C to 20 DEG C, is slowly added dropwise 2-(the 2-chlorine being dissolved in 200ml oxolane
For ethyoxyl) chloroacetic chloride 31.2g(0.2mol), dropping process temperature controls at 10 DEG C to 20 DEG C, and time for adding controls
At 3 hours, drip and finish, TLC is controlled (n-hexane: ethyl acetate: triethylamine=30:20:1, volume ratio) raw material and substantially disappears
Losing, stopped reaction, decompression (-0.1MPa～-0.09MPa) is evaporated off oxolane and reclaims the Isosorbide-5-Nitrae-diaminobenzene of excess,
Adding 400ml ethyl acetate and the mixed solvent of 200ml acetone, temperature rising reflux dissolves residual grease, is down to 10 DEG C
Left and right crystallize 5 hours, filters, decompression drying, obtains off-white color intermediate III product 41.8g, molar yield 91.7%,
HPLC purity 97.8%.
The detection data of the title product obtained by nuclear magnetic resonance, NMR and mass spectral analysis are as follows:1H NMR (400MHz,
CDCl3): δ=7.39 (d, 2H), 7.24(s, 1H), 6.59 (d, 2H), 6.25 (s, 2H), 4.30 (s, 2H), 3.83 (t,
2H), 3.66 (t, 2H)；13C NMR (75MHz, CDCl3): δ=169.2,144.1,128.5,122.3,122.3,116.5,
116.5,68.5,68.2,42.3ppm；HR-MS (ESI): C10H13ClN2O2Molecular weight: 228.1, [M+H]+Measured value:
229.3。
The preparation of embodiment 3:4-(4-aminophenyl)-3-morpholone (formula IV):
Reaction bulb adds the 45.6g(0.2mol of embodiment 1 preparation) N-(4-aminophenyl)-2-(2-Chloroethoxy)
Acetamide (formula III), 250ml dichloromethane, 82.8g(0.6mol) potassium carbonate, 6.4g(0.02mol) tetrabutyl bromine
Changing ammonium, stir, reaction system is cooled to 0 DEG C to 20 DEG C, insulated and stirred 5 hours, controls (dichloromethane in TLC
Alkane: methanol=20:1, volume ratio), raw material disappears substantially.Being filtered to remove insoluble matter, organic layer purifies washing with 80ml
Washing, separatory, organic layer decompression (-0.08MPa～-0.06MPa) is evaporated, and adds 150ml acetone and stirs 3 hours,
Separate out crystal, filter, decompression drying, obtain 4-(4-aminophenyl)-3-morpholone 35.2g, molar yield 91.6%,
HPLC purity 98.5%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI): C10H12N2O2 molecular weight: 192.1,
[M+H]+Measured value: 193.5.
The preparation of embodiment 4:4-(4-aminophenyl)-3-morpholone (formula IV):
Reaction bulb adds the 34.2g(0.15mol of embodiment 2 preparation) N-(4-aminophenyl)-2-(2-Chloroethoxy)
Acetamide (formula III), 200ml dichloromethane, 62.1g(0.45mol) potassium carbonate, 4.8g(0.015mol) tetrabutyl
Ammonium bromide, stirs, and reaction system is cooled to 0 DEG C to 20 DEG C, insulated and stirred 3 hours, controls (dichloro in TLC
Methane: methanol=20:1, volume ratio), raw material disappears substantially.It is filtered to remove insoluble matter, organic layer 60ml purified water
Washing, separatory, organic layer decompression (-0.08MPa～-0.06MPa) is evaporated, and adds 110ml acetone and stirs 3 hours,
Separate out crystal, filter, decompression drying, obtain 4-(4-aminophenyl)-3-morpholone 26.6g, molar yield 92.4%,
HPLC purity 98.2%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI): C10H12N2O2Molecular weight: 192.1,
[M+H]+Measured value: 193.7.
Embodiment 5:4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazoles alkane-3-base] phenyl } morpholine-3-ketone (formula
VII) preparation:
Reaction bulb adds the 32.7g(0.17mol of embodiment 3 preparation) 4-(4-aminophenyl)-3-morpholone (formula IV),
64.4g(0.70mol) (R)-2-(chloromethyl) oxirane and 600ml isopropanol, stir, be warming up to backflow anti-
Answer 17 hours, TLC is controlled (dichloromethane: methanol=20:1, volume ratio) reaction and completely, reactant liquor is concentrated to give
Intermediate V crude product, adds 300ml acetone temperature rising reflux 20 minutes, Temperature fall stirring and crystallizing 3 hours, mistake
Filter, decompression drying, obtain intermediate V about 42.6g(0.15mol), intermediate compound IV prepares mole receipts of intermediate V
Rate about 88.2%.
In reaction bulb, by the 42.6g(0.15mol of gained) intermediate V 400ml absolute methanol dissolving, add subsequently
Enter 38.8g(0.21mol) phthalimide potassium, temperature rising reflux 10 hours, in TLC control (ethyl acetate:
Methanol=10:1, volume ratio) react completely, heat filtering, filtrate is down to room temperature (about 25 DEG C) stirring 2 hours, mistake
Filter, filter cake 100ml absolute methanol drip washing, decompression drying, obtain off-white color intermediate VI about 51.4g(0.13mol),
Intermediate V prepares the molar yield about 86.7% of intermediate VI.
Reaction bulb adds the 51.4g(0.13mol of gained) intermediate VI, 300ml oxolane, 84.3g(0.52mol)
N, N '-carbonyl dimidazoles stirs, and adds the DMAP (DMAP) of 6.5g, and temperature rising reflux 12 is little
Time, TLC is controlled (dichloromethane: methanol=20:1, volume ratio) reaction completely, stopped reaction, stirs after being down to room temperature
Mixing 1 hour, filter, 95% ethanol of filter cake 50ml oxolane and 100ml washs successively, and gained wet product is straight
Connect and put into reaction bulb, and add 95% ethanol of 500ml and the 30-33% methylamine water solution of 110ml, stir,
Temperature rising reflux 8 hours, controls (dichloromethane: methanol=20:1, volume ratio) reaction and completely, is down to room temperature, use in TLC
37% hydrochloric acid (V/V) regulation pH to 1-2, separates out a large amount of white solid, filters, 95% second of filter cake 50ml
Alcohol drip washing.Decompression drying, the 39.2g(0.12mol obtained) off-white color solid is the hydrochlorate of intermediate VII, in
Mesosome VI prepares the molar yield about 92.2% of intermediate VII, HPLC purity 99.3%.
By 39.2g(0.12mol) intermediate VII hydrochlorate join 200ml purified water and 200ml dichloromethane
In, under stirring, with sodium carbonate regulation pH value to about 8, separatory, organic layer is evaporated, and obtains intermediate VII oily
Thing 33.2g(0.114mol), solve salt molar yield 95.0%, HPLC purity 98.2%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI): C14H17N3O4Molecular weight: 291.1,
[M+H]+Measured value: 292.5.
Embodiment 6:4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazoles alkane-3-base] phenyl } morpholine-3-ketone (formula
VII) preparation:
Reaction bulb adds the 24.5g(0.128mol of embodiment 4 preparation) 4-(4-aminophenyl)-3-morpholone (formula IV),
48.3g(0.525mol) (R)-2-(chloromethyl) oxirane and 450ml isopropanol, stir, and is warming up to backflow
React 17 hours, TLC is controlled (dichloromethane: methanol=20:1, volume ratio) reaction and completely, reactant liquor is concentrated to give
To intermediate V crude product, add 220ml acetone temperature rising reflux 20 minutes, Temperature fall stirring and crystallizing 3 hours,
Filter, decompression drying, obtain intermediate V about 32.7g(0.115mol), intermediate compound IV prepares rubbing of intermediate V
That yield about 89.8%.
In reaction bulb, by the 32.7g(0.115mol of gained) intermediate V 300ml absolute methanol dissolving, subsequently
Add 29.1g(0.157mol) phthalimide potassium, temperature rising reflux 9 hours, in TLC control (acetic acid
Ethyl ester: methanol=10:1, volume ratio) reaction completely, heat filtering, filtrate is down to room temperature (about 25 DEG C) and stirs 2 hours,
Filter, filter cake 75ml absolute methanol drip washing, decompression drying, obtain off-white color intermediate VI about 39.9g(0.101mol),
Intermediate V prepares the molar yield about 87.8% of intermediate VI.
Reaction bulb adds the 39.9g(0.101mol of gained) intermediate VI, 100ml oxolane, 63.2g(0.39mol)
N, N '-carbonyl dimidazoles stirs, and adds the DMAP (DMAP) of 5.0g, and temperature rising reflux 10 is little
Time, TLC is controlled (dichloromethane: methanol=20:1, volume ratio) reaction completely, stopped reaction, stirs after being down to room temperature
Mixing 1 hour, filter, 95% ethanol of filter cake 40ml oxolane and 70ml washs successively, and gained wet product is direct
Put into reaction bulb, and add 95% ethanol of 400ml and the 30-33% methylamine water solution of 80ml, stir, rise
Temperature backflow 8 hours, controls (dichloromethane: methanol=20:1, volume ratio) reaction and completely, is down to room temperature, use in TLC
37% hydrochloric acid (V/V) regulation pH to 1-2, separates out a large amount of white solid, filters, 95% second of filter cake 40ml
Alcohol drip washing.Decompression drying, the 29.3g(0.09mol obtained) off-white color solid is the hydrochlorate of intermediate VII, in
Mesosome VI prepares the molar yield about 89.1% of intermediate VII hydrochlorate, HPLC purity 99.4%.
By 29.3g(0.09mol) intermediate VII hydrochlorate join 150ml purified water and 150ml dichloromethane
In, under stirring, with sodium carbonate regulation pH value to about 8, separatory, organic layer is evaporated, and obtains intermediate VII oily
Thing 25.3g(0.087mol), solve salt molar yield 96.7%, HPLC purity 98.5%.
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI): C14H17N3O4Molecular weight: 291.1,
[M+H]+Measured value: 291.2.
The preparation of embodiment 7: Li Daishaban:
Reaction bulb adds the 20.4g(0.07mol of embodiment 5 preparation) 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,
3-oxazolidine-3-base] phenyl morpholine-3-ketone (Formula VII), the DMF of 200ml, 10g triethylamine,
Stir, at 20 DEG C to 30 DEG C, drip 12.6g(0.07mol) 2-chloroformyl-5-chlorothiophene, drips and finishes, continue insulation
React 5 hours at 20 DEG C to 30 DEG C, TLC is controlled (dichloromethane: methanol=20:1, volume ratio) reaction completely, will
Reactant liquor is poured in 500ml purified water, has a large amount of solid to separate out, and stirs 1 hour, filters, and filter cake 100ml is pure
Change water washing, decompression drying, obtain razaxaban product 26.1g(0.060mol), molar yield 85.7%, HPLC
Purity 99.6%
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI): C19H18ClN3O5S molecular weight:
435.1, [M+H]+Measured value: 436.8.
The preparation of embodiment 8: Li Daishaban:
Reaction bulb adds the 20.4g(0.07mol of embodiment 6 preparation) 4-{4-[(5S)-5-(amino methyl)-2-oxo-1,
3-oxazolidine-3-base] phenyl morpholine-3-ketone (Formula VII), the DMF of 200ml, 10g triethylamine,
Stir, at 20 DEG C to 30 DEG C, drip 14.4g(0.08mol) 2-chloroformyl-5-chlorothiophene, drips and finishes, continue insulation
React 5 hours at 20 DEG C to 30 DEG C, TLC is controlled (dichloromethane: methanol=20:1, volume ratio) reaction completely, will
Reactant liquor is poured in 500ml purified water, has a large amount of solid to separate out, and stirs 1 hour, filters, and filter cake 100ml is pure
Change water washing, decompression drying, obtain razaxaban product 25.3g(0.058mol), molar yield 82.9%, HPLC
Purity 99.5%
The detection data of the title product that mass spectral analysis obtains are as follows: HR-MS (ESI): C19H18ClN3O5S molecular weight:
435.1, [M+H]+Measured value: 436.4.
Claims (13)
1. the compound shown in formula III:
Wherein, X is halogen.
Compound shown in formula III the most according to claim 1, it is characterised in that described X is chlorine or bromine.
3. the method preparing the compound shown in formula III, including: with the compound Isosorbide-5-Nitrae-diaminourea shown in Formulas I
Compound 2-(2-halo ethyoxyl) acetyl halide shown in benzene and Formula II is initiation material, adds acid binding agent, through singly taking
For obtaining the compound shown in formula III after reaction:
Wherein, X is halogen.
Method the most according to claim 3, it is characterised in that described X is chlorine or bromine.
Method the most according to claim 3, it is characterised in that described acid binding agent is pyridine or 4-diformazan ammonia
Yl pyridines.
Method the most according to claim 3, it is characterised in that the solvent of described single substitution reaction is aprotic
Solvent, one or more in the following solvent of described non-protonic solvent: oxolane, chloroform, dichloromethane,
Benzene, toluene and ether.
Method the most according to claim 3, it is characterised in that described initiation material Isosorbide-5-Nitrae-diaminobenzene and 2-(2-
Halo ethyoxyl) mol ratio of acetyl halide is 3～30: 1.
Method the most according to claim 7, it is characterised in that described initiation material Isosorbide-5-Nitrae-diaminobenzene and 2-(2-
Halo ethyoxyl) mol ratio of acetyl halide is 5～10: 1.
Method the most according to claim 3, it is characterised in that the reaction temperature of described single substitution reaction is 0 DEG C
～50 DEG C.
Method the most according to claim 9, it is characterised in that the reaction temperature of described single substitution reaction is 10 DEG C
～20 DEG C.
11. according to the arbitrary described method of claim 3～10, it is characterised in that the method specifically: by Isosorbide-5-Nitrae-
Diaminobenzene and acid binding agent are dissolved in reaction dissolvent, then drip 2-(2-halo ethyoxyl) acetyl halide solution and singly take
Generation reaction, time for adding is 1～10 hour.
12. methods according to claim 11, it is characterised in that dropping 2-(2-halo ethyoxyl) acetyl halide
The time of solution is 2～5 hours.
The application in preparing razaxaban of the compound shown in formula III described in 13. claim 1 or 2.
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| WO2006055951A2 (en) * | 2004-11-19 | 2006-05-26 | Portola Pharmaceuticals, Inc. | Tetrahydroisoquinolines as factor xa inhibitors |
| CN1852902A (en) * | 2003-09-15 | 2006-10-25 | 拜耳医药保健股份公司 | Method for the production of 4-(4-aminophenyl)-3-morpholinon |
| WO2009023233A1 (en) * | 2007-08-14 | 2009-02-19 | Concert Pharmaceuticals, Inc. | Substituted oxazolidinone derivatives |
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| CN1852902A (en) * | 2003-09-15 | 2006-10-25 | 拜耳医药保健股份公司 | Method for the production of 4-(4-aminophenyl)-3-morpholinon |
| WO2006055951A2 (en) * | 2004-11-19 | 2006-05-26 | Portola Pharmaceuticals, Inc. | Tetrahydroisoquinolines as factor xa inhibitors |
| WO2009023233A1 (en) * | 2007-08-14 | 2009-02-19 | Concert Pharmaceuticals, Inc. | Substituted oxazolidinone derivatives |
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